The present invention relates to a compound having an aldose reductase inhibitory activity and more specifically to a tetrazoleacetic acid derivative and an aldose reductase inhibitor which comprises the tetrazoleacetic acid derivative as an effective component and which is effective as a preventive medicine and/or remedy for diabetic complications as well as a method for alleviating or reducing diabetic complications.
It has been known that aldose reductase inhibitors are effective for prevention and/or treatment of diabetic complications. This is detailed in the article of Dr. Tsuyoshi TANIMOTO [Division of Biological Chemistry and Reference Standards, National Institute of Hygienic Sciences] Farumashia, 1988, 24, No. 5, pp. 459-463).
This article discloses the chemical structures and 50% inhibitory concentrations (IC.sub.50) of representative aldose reductase inhibitors such as Alrestatin, Tolrestat, 4-Isopropyl-BPOC, Sorbinil, M-79175, Alconil, ADN-138, Epalrestat, CT-112 and Statil.
Metabolism, 28:456 (1979) and Jap. J. Opthalmol., 20:399 (1976) report that sorbitol accumulates in the lens or peripheral nerves of a patient suffering from diabetes by the action of aldose reductase, whereby causing diabetic complications.
The inventors of this invention have already conducted screening of novel aldose reductase inhibitors, found that tetrazoleacetic acid derivatives have very high aldose reductase inhibitory activity, and filed four patent applications. Among them, two patents were granted (U.S. Pat. Nos. 5,055,481 and 5,068,239). The other two are now pending (U.S. Ser. Nos. 07/821,456 and 07/857,400).
The co-inventors of the present application reported that a compound having a high aldose reductase inhibitory activity and having the general formula (III): ##STR2## wherein R.sub.1 means a ring of pyridine, pyrrole, furan, thiophene, benzofuran, benzothiophene, etc., by treating R.sub.1 CONHCH.sub.2 COOR.sub.2 (R.sub.1 is defined above) with PCl.sub.5 or SOCl.sub.2 in N, N-dimethylformamide (DMF), and then reacting the resultant compound with NaN.sub.3 in DMF (Abstracts of The Papers at The 111th Anual Meeting of The Pharmaceutical Society of Japan, No. 2:220 (29 V), published on Mar. 5, 1991).
However, according to this method, a compound having the general formula (III), wherein an OR group (R is H or lower alkyl group) is introduced into the group R.sub.2, was not able to be produced. In addition, the present inventors have found that by introducing the OR group into the R.sub.2 group of the general formula (III), there is obtained a new 5-substituted tetrazoleacetic acid derivative which exhibits an aldose reductase inhibitory activity equivalent to or much higher than that of the compound wherein the OR group is not introduced into the R.sub.2 group.